Gout presentation
How is uric acid excretion different for those with gout vs non when plasma urate levels are raised? **
in those with gout, plasma urate concentrations must be 60-120 μmol/L (1-2 mg/dL) higher than normal to achieve equivalent uric acid excretion rates.
What is the name of one organic anion transporter that the kidney uses to clear urate from the plasma and maintain physiologic balance? **
urate transporter 1 (URAT1)
What is the 4 components model for the renal handling of urate/ uric acid? **
(1) glomerular filtration, (2) tubular reabsorption, (3) secretion, and (4) postsecretory reabsorption. Note: used to be considered seqential - now we know these processes are CARRIED OUT IN PARALLEL.
What are the important causes of hyperuricemia due to urate overproduction?**
-- HPRT deficiency -- PRPP synthetase overactivity -- Hemolytic processes -- Lymphoproliferative diseases -- Rhabdomyolysis -- Alcohol -- Purine-rich diet
Describe the most common clinical presentation of a patient who presents with gout in terms of appearance of joints
-- The first episode of acute gouty arthritis frequently begins at night with dramatic joint pain and swelling. -- Joints rapidly become warm, red, and tender. -- Early attacks tend to subside spontaneously within 3-10 days
More than 90% of individuals with sustained hyperuricemia have what defect?**
-- defect in the renal handling of uric acid.
What influences urate production? **
-- dietary intake of purines and -- the rates of de novo biosynthesis of purines from nonpurine precursors, -- nucleic acid turnover, -- nucleic acid salvage by phosphoribosyltransferase activities.
What is the only method available to accurately distinguish between septic arthritis, gout and CPPD? **
-- evaluation of synovial fluid is the only method available to accurately distinguish between septic arthritis, gout, and CPPD Note: Before the use of crystallographic techniques in rheumatology, much of what was considered to be gouty arthritis in fact was not. Because of often similar clinical presentations, the need to perform synovial fluid analysis to distinguish the type of crystal involved must be emphasized.
What are the important causes of hyperuricemia due to urate overproduction and decreased uric acid excretion combined?**
-- glucose-6-phosphate deficiency -- alcohol
Sustained hyperuricemia can predispose some individuals to develop what clinical manifestations? **
-- gouty arthritis -- urolithiasis -- renal dysfunction
What are the relatively common abnormalities of nucleotide metabolism? **
-- hyperuricemia -- gout
What medications are associated with uricosuric activity? **
-- probenecid
What are the important causes of hyperuricemia due to decreased uric acid excretion?**
-- renal insufficiency -- acidosis -- diuretics -- alcohol
What is the role of purines and pyrimidines in the body? **
-- replication of genetic material, -- gene transcription, -- protein synthesis, and -- cellular metabolism
Why is it important to aspirate and analyze synovial fluid? **
-- to distinguish the crystal involved -- to assess the possibility of infection
Be able to describe the clinical characteristics of Lesch-Nyhan syndrome:
A complete deficiency of HPRT, the Lesch-Nyhan syndrome, is characterized by: -- hyperuricemia, -- self-mutilative behavior, -- choreoathetosis, -- spasticity -- mental retardation. Note: the hyperuricemia results from urate overproduction and can cause uric acid crystalluria, nephrolithiasis, obstructive uropathy, and gouty arthritis.
When is urine saturated with uric acid at pH 5?**
At pH 5.0, urine is saturated with uric acid at concentrations ranging from 360 to 900 μmol/L (6-15 mg/dL). Note: more acid conditions cause the urine to become saturated at a much lower level of uric acid. --> more likely to produce supersaturation at lower pH - with the risk that the urate crystals with precipitate out.
When is urine saturated with uric acid at pH 7?**
At pH 7, saturation is reached at concentrations between 9480 and 12,000 μmol/L (158 and 200 mg/dL).
How is a presumptive diagnosis of gout confirmed? **
Even if the clinical appearance strongly suggests gout, the presumptive diagnosis ideally should be confirmed by needle aspiration of acutely or chronically involved joints or tophaceous deposits.
1.Describe the most common clinical presentation of a patient who presents with gout in terms of age
Gout is a metabolic disease that most often affects -- middle-aged to elderly men and -- postmenopausal women.
Describe the most common clinical presentation of a patient who presents with gout in terms of sex
Gout is a metabolic disease that most often affects -- middle-aged to elderly men and -- postmenopausal women. Note: Women represent only 5-20% of all patients with gout. Premenopausal gout is rare; it is seen mostly in individuals with a strong family history of gout
5.List the extraarticular manifestations associated with hyperuricemia that are specific to the kidney.
Hyperuricemia also causes several renal problems: (1) nephrolithiasis; (2) urate nephropathy, a rare cause of renal insufficiency attributed to monosodium urate crystal deposition in the renal interstitium. (3) uric acid nephropathy, a reversible cause of acute renal failure resulting from deposition of large amounts of uric acid crystals in the renal collecting ducts, pelvis, and ureters.
3.Describe the underlying mechanisms that result in patients developing hyperuricemia. Specifically, think about how hyperuricemia can result from over production, under excretion, or a combination of over production and under excretion of uric acid.
Hyperuricemia can result from -- increased production of urate -- decreased excretion of urate -- or a combination of both mechanisms. When hyperuricemia exists, urate can precipitate and deposit in tissues as tophi.
What is the most useful way to classify types of hyperuricemia?**
In relation to the underlying pathophysiology: Hyperuricemia resulting from: -- increased production -- decreased excretion -- combination of both
What host defense process leads to the symptoms of gout and CPPD?
Monosodium Urate Crystals or Calcium Pyrophosphate Dihydrate Crystals must undergo phagocytosis by synovial neutrophils which then release inflammatory cytokines such as lysosomal enzymes and interleukins that cause inflammation, and thus, the symptoms of gout and CPPD
How much urate is normally excreted by the kidneys? **
Normally, two-thirds to three-fourths of urate is excreted by the kidneys
List the clinical characteristics of PRPP synthetase overactivity:
PRPP synthetase overactivity is X-linked and results in gouty arthritis and uric acid nephrolithiasis.
2.Describe common preceding events that are associated with acute gout attacks.
Several events may precipitate acute gouty arthritis: -- dietary excess, -- trauma, -- surgery, -- excessive ethanol ingestion, -- hypouricemic therapy, and -- serious medical illnesses such as myocardial infarction and stroke.
What is the mechanism by which many agents cause hyperuricemia via the kidney? **
Stimulating reabsorption --> NOT by inhibiting secretion.
6.Several genetic conditions can result in purine and pyrimidine metabolism disorders. These disorders often result in hyperuricemia. List the pathologic mechanism of Lesch-Nyhan syndrome
The HPRT gene is located on the X chromosome. Affected males are hemizygous for the mutant gene; carrier females are asymptomatic. A complete deficiency of HPRT, results in Lesch-Nyhan syndrome. Note: there is excess uric acid production because you are unable to salvage Hypozanthine --> IMP or Guanine --> GMP. So these go down a different pathway where XO makes them into uric acid.
Describe the most common clinical presentation of a patient who presents with gout in terms of type of joints affected
The metatarsophalangeal joint of the first toe often is involved, but tarsal joints, ankles, and knees also are affected commonly.
How do carboxylates cause hyperuricemia? **
The mono- and divalent anions become substrates for URAT1 and organic anion transporter (OAT4), respectively, and are exchanged for uric acid from the proximal tubule. Increased blood levels of these anions result in their increased glomerular filtration and greater reabsorption by proximal tubular cells. The increased intraepithelial cell concentrations lead to increased uric acid reabsorption by promoting URAT1- and OAT4-dependent anion exchange.
What determines the total body urate pool? **
The total-body urate pool is the net result between urate production and excretion.
4.Apply your knowledge of the mechanisms involved in the development of hyperuricemia to assess the underlying pathologic mechanisms of patients who present with gout. Specifically, be familiar with the causes of hyperuricemia highlighted in Table 359-2.
Urate overproduction --> hyperuricemia - HPRT deficiency - PRPP synthetase overactivity - Hemolytic processes - Lymphoproliferative diseases - Rhabdomyolysis - Alcohol - Purine-rich diet Decreased Uric acid excretion --> hyperuricemia - Renal insufficiency - Acidosis - Diuretics - Alcohol Combined Increased urate production adn decreased uric acid excretion --> hyperuricemia - Glucose-6-phosphatase deficiency GSD type I (von Gierke disease) - Alcohol
What causes variation in the production of urate? **
Urate production varies with the purine content of the diet and the rates of purine biosynthesis, degradation, and salvage ( Fig . 359 - 1).
What form of uric acid is predominant in the plasma extracellular fluid and synovial fluid? **
Urates, the ionized forms of uric acid, predominate in plasma extracellular fluid and synovial fluid, with ∼98% existing as monosodium urate at pH 7.4.
How does uric acid excretion change when plasma urate levels are raised? **
Uric acid excretion increases in gouty and nongouty individuals when plasma urate levels are raised.
Where does uric acid come from? **
Uric acid is the final breakdown product of purine degradation in humans.
What is cis-inhibition of the URAT-1 transporter? What causes it? **
Uricosuric compounds ( Table 359 - 1) directly inhibit URAT1 on the apical side of the tubular cell (so-called cis-inhibition).
Describe the most common clinical presentation of a patient who presents with gout in terms of number of joints affected
Usually, only one joint is affected initially, but polyarticular acute gout can occur in subsequent episodes. Note: After many acute mono- or oligoarticular attacks, a proportion of gouty patients may present with a chronic nonsymmetric synovitis. DDX RA.
What is the mechanism by which alcohol promotes hyperuricemia?
Via increased urate productio and decreased uric acid excretion. -- Excessive alcohol consumption accelerates hepatic breakdown of ATP to increase urate production. -- Alcohol consumption can also induce hyperlacticacidemia, which blocks uric acid secretion. -- The higher purine content in some alcoholic beverages such as beer may also be a factor.
How are plasma urate levels raised? **
by purine ingestion or infusion
What causes the episodic acute and chronic arthritis in gout?
deposition of MSU crystals in: - joints - connective tissue tophi The risk for deposition in: - kidney interstitium or uric acid nephrolithiasis
What creates the potential for urate crystal precipitation?**
supersaturation of monosodium urate in the plasma.
